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(1 - 9 of 9)
- Title
- Deciphering the Role of Adrenergic Hormones in Embryonic Cardiac Calcium Signaling and Metabolism.
- Creator
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Peoples, Jessica, Ebert, Steven, Davidson, Victor, Phanstiel, Otto, Yooseph, Shibu, University of Central Florida
- Abstract / Description
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The adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are critical regulators of mammalian cardiovascular physiology. NE and EPI mediate stress responses to enhance cardiovascular function, however dysregulation of adrenergic signaling leads to heart failure, congenital heart malformations, and sudden cardiac death. Adrenergic hormone-expressing cells were found in the early embryonic heart, and NE has been determined essential for embryonic cardiac development. Despite extensive...
Show moreThe adrenergic hormones norepinephrine (NE) and epinephrine (EPI) are critical regulators of mammalian cardiovascular physiology. NE and EPI mediate stress responses to enhance cardiovascular function, however dysregulation of adrenergic signaling leads to heart failure, congenital heart malformations, and sudden cardiac death. Adrenergic hormone-expressing cells were found in the early embryonic heart, and NE has been determined essential for embryonic cardiac development. Despite extensive work in adults, the regulatory roles and adrenergic targets of these hormones during embryonic cardiac development have not yet been fully determined. Prior transcriptomic studies from our lab showed that expression of signal transduction and metabolic genes in embryos lacking adrenergic hormones were by far the most affected categories of genes. Thus, we hypothesized that adrenergic hormones stimulate early calcium signaling, and are required for sufficient supply of energy substrates for the metabolic shift from anaerobic glycolysis to aerobic respiration during heart development. We utilized the dopamine ?-hydroxylase knock-out (Dbh-/-) mouse model to examine effects of adrenergic-deficiency on calcium signaling and metabolism during heart development. Using calcium-imaging and patch-clamp techniques, we found that calcium transients, voltage-gated calcium channels, and L-type calcium currents in adrenergic-deficient embryonic hearts were not affected relative to controls indicating adrenergic stimulation did not influence early calcium signaling. Metabolomics analyses of adrenergic-deficient hearts revealed disruption in glycolytic and pentose-phosphate pathways as well as reduced activity of respective regulatory enzymes, glyceraldehyde 3-phosphate dehydrogenase and glucose 6-phosphate dehydrogenase indicating compromised glucose metabolism. Addition of pyruvate to embryonic hearts led to significant recovery of ATP concentrations and oxygen consumption rates, thereby supporting the hypothesis that adrenergic-deficient hearts are (")starved(") of metabolic substrates required for transitions from anaerobic glycolysis to aerobic metabolism. Overall, we showed that adrenergic hormones are not necessary for calcium signaling in the embryonic heart, but are essential regulators ensuring sufficient metabolic substrate and boosting enzymatic activities to fuel aerobic metabolism.
Show less - Date Issued
- 2018
- Identifier
- CFE0007233, ucf:52223
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007233
- Title
- Membrane topology of a broad-spectrum resistance factor responsible for lipid modification in Enterococcus faecium.
- Creator
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Harrison, Jesse, Roy, Herve, Teter, Kenneth, Phanstiel, Otto, University of Central Florida
- Abstract / Description
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Aminoacylphosphatidylglycerol synthases (aaPGSs) are integral membrane proteins that use aminoacyl-tRNAs as substrates to catalyze the addition of amino acids to phosphatidylglycerol (PG) in the cytoplasmic membranes of bacteria. Addition of amino acids to PG decreases the net negative charge of the membrane, conferring resistance to various classes of antibacterial agents (i.e., cationic antimicrobial peptides, beta-lactams, glycopeptides, and lipopeptides) and protecting the cell against...
Show moreAminoacylphosphatidylglycerol synthases (aaPGSs) are integral membrane proteins that use aminoacyl-tRNAs as substrates to catalyze the addition of amino acids to phosphatidylglycerol (PG) in the cytoplasmic membranes of bacteria. Addition of amino acids to PG decreases the net negative charge of the membrane, conferring resistance to various classes of antibacterial agents (i.e., cationic antimicrobial peptides, beta-lactams, glycopeptides, and lipopeptides) and protecting the cell against osmotic stress and acidic conditions. aaPGS homologs are found in a variety of clinically relevant microorganisms, including Enterococcus faecium, which is increasingly found to be the etiologic agent of antibiotic-resistant nosocomial infections. Although the broad distribution of these virulence factors across bacterial species makes them attractive targets for therapeutic strategies, little is known about the structure of aaPGSs. Two aaPGS paralogs are found in E. faecium, one of which exhibits relaxed substrate specificity and is responsible for the transfer of Arg (R), Ala (A), and Lys (K) to PG (RakPGS). The catalytic site of RakPGS is located in the hydrophilic C-terminal domain, which is localized in the cytoplasm. The N-terminus contains an integral membrane domain that is thought to harbor flippase activity that translocates the neosynthesized aa-PG from the inner to the outer leaflet of the membrane. We are currently developing the substituted cysteine accessibility method (SCAM) and a dual-reporter fusion system, which exploits alkaline phosphatase (Pho) and ?-galactosidase (LacZ) activities, for investigating the membrane topology of RakPGS in E. faecium.
Show less - Date Issued
- 2015
- Identifier
- CFE0006318, ucf:51566
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006318
- Title
- The development of motuporamine derivatives and an investigation into their biological properties.
- Creator
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Skruber, Kristen, Phanstiel, Otto, Teter, Kenneth, Vonkalm, Laurence, University of Central Florida
- Abstract / Description
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This project investigates the synthesis of a class of compounds derived from a marine-based natural product and probes how iterative changes to its structure affect its derivatives' biological efficacy. The compound class of interest are the motuporamines which were isolated from the sea sponge Xestospongia exigua collected off the coast of Motupore island in Papua, New Guinea. The compounds for this project are predicated upon dihydromotuporamine C (Motu33), the compound that has been shown...
Show moreThis project investigates the synthesis of a class of compounds derived from a marine-based natural product and probes how iterative changes to its structure affect its derivatives' biological efficacy. The compound class of interest are the motuporamines which were isolated from the sea sponge Xestospongia exigua collected off the coast of Motupore island in Papua, New Guinea. The compounds for this project are predicated upon dihydromotuporamine C (Motu33), the compound that has been shown to be both cytotoxic to MDA-MB231 breast carcinoma cells and has antimetastatic efficacy. The motuporamine scaffold contains a large fifteen-membered saturated macrocycle and an appended polyamine component. A series of Motu33 derivatives were synthesized and evaluated for their ability to target the polyamine transport system as well as inhibit cell migration of human pancreatic cancer cells in vitro. By altering the polyamine component of the system we attempted to build smart antimetastatic compounds which target the upregulated polyamine transport system of human pancreatic cancers and block their migration.
Show less - Date Issued
- 2016
- Identifier
- CFE0006505, ucf:51390
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0006505
- Title
- The Anti-toxin Properties of Grape Seed Phenolic Compounds.
- Creator
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Cherubin, Patrick, Teter, Kenneth, Zervos, Antonis, Roy, Herve, Phanstiel, Otto, University of Central Florida
- Abstract / Description
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Corynebacterium diphtheriae, Pseudomonas aeruginosa, Ricinus communis, Shigella dysentariae, and Vibrio cholerae produce AB toxins which share the same basic structural characteristics: a catalytic A subunit attached to a cell-binding B subunit. All AB toxins have cytosolic targets despite an initial extracellular location. AB toxins use different methods to reach the cytosol and have different effects on the target cell. Broad-spectrum inhibitors against these toxins are therefore hard to...
Show moreCorynebacterium diphtheriae, Pseudomonas aeruginosa, Ricinus communis, Shigella dysentariae, and Vibrio cholerae produce AB toxins which share the same basic structural characteristics: a catalytic A subunit attached to a cell-binding B subunit. All AB toxins have cytosolic targets despite an initial extracellular location. AB toxins use different methods to reach the cytosol and have different effects on the target cell. Broad-spectrum inhibitors against these toxins are therefore hard to develop because they use different surface receptors, entry mechanisms, enzyme activities, and cytosolic targets.We have found that grape seed extract provides resistance to five different AB toxins: diphtheria toxin (DT), P. aeruginosa exotoxin A (ETA), ricin, Shiga toxin, and cholera toxin (CT). To identify individual compounds in grape seed extract that are capable of inhibiting the activities of these AB toxins, we screened twenty common phenolic compounds of grape seed extract for anti-toxin properties. Three compounds inhibited DT, four inhibited ETA, one inhibited ricin, and twelve inhibited CT. Additional studies were performed to determine the mechanism of inhibition against CT. Two compounds inhibited CT binding to the cell surface and even stripped bound CT off the plasma membrane of a target cell. Two other compounds inhibited the enzymatic activity of CT. We have thus identified individual toxin inhibitors from grape seed extract and some of their mechanisms of inhibition against CT. This work will help to formulate a defined mixture of phenolic compounds that could potentially be used as a therapeutic against a broad range of AB toxins.
Show less - Date Issued
- 2014
- Identifier
- CFE0005315, ucf:50510
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0005315
- Title
- High Pressure Micro-Spectroscopy of Biological Assemblies and Cells.
- Creator
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Park, Sang, Schulte, Alfons, Chow, Lee, Luo, Weili, Phanstiel, Otto, University of Central Florida
- Abstract / Description
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Functional properties of living cells depend on the thermodynamic variables such as temperature and pressure. A unique tool to investigate volume effects on structure and metabolism of the cell and biomolecules is pressure perturbation. We have developed a new setup that enables micro-spectroscopy and optical imaging of individual live cells at variable pressure from 0.1 to 400 MPa. Following characterization of the setup, pressure and temperature effects on the secondary structure of the...
Show moreFunctional properties of living cells depend on the thermodynamic variables such as temperature and pressure. A unique tool to investigate volume effects on structure and metabolism of the cell and biomolecules is pressure perturbation. We have developed a new setup that enables micro-spectroscopy and optical imaging of individual live cells at variable pressure from 0.1 to 400 MPa. Following characterization of the setup, pressure and temperature effects on the secondary structure of the peptide Poly-L-glutamic acid (PGA) in deuterated water buffer solution were investigated. The amide I band of PGA is sensitive to pressure and temperature, and by spectral deconvolution, we determined the relative contributions due to the ?-helix and random coil conformations. The population of ?-helix increases with increasing pressure. Pressure effects on single red blood cells and the intracellular protein hemoglobin were studied by micro-Raman spectroscopy. In particular, we observed a shift in the frequency of the iron-histidine vibrational band in both the intracellular hemoglobin and hemoglobin in solutions. The iron-histidine mode is a sensitive structural marker of the crucial iron-protein linkage in heme proteins. The pressure dependent shift suggests a conformational change of the heme environment. This finding was further supported by micro-absorption measurements at variable pressure.In additional experiments, Raman spectroscopy was employed to probe molecular changes that occurred in hemoglobin in erythrocytes infected with the malaria parasite Plasmodium falciparum. The spectra of infected cells indicated that hemoglobin degradation can be correlated with the stages of the parasite multiplication cycle. The research was further extended towards probing size and shape changes of individual cells with pressure. The lateral diameter in yeast cells was observed to decrease with pressure in a reversible way. These results suggest that transport of the intra-cellular water may play a significant role for volume changes.In summary, pressure changes were shown to induce conformational changes in proteins and shape changes in yeast cells. A Raman technique was developed to monitor the states of Plasmodium falciparum multiplication cycle within a red blood cell.
Show less - Date Issued
- 2012
- Identifier
- CFE0004637, ucf:49909
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0004637
- Title
- A chemical and genetic approach to study the polyamine transport system in Drosophila.
- Creator
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Wang, Minpei, Vonkalm, Laurence, Phanstiel, Otto, Teter, Kenneth, Ballantyne, John, University of Central Florida
- Abstract / Description
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Polyamines are small cationic molecules that play important roles in most vital cellular processes including cell growth and proliferation, regulation of chromatin structure, translation and programmed cell death. Cellular polyamine pools are maintained by a balance between biosynthesis and transport (export and import). Increased polyamine biosynthesis activity and an active transport system are characteristics of many cancer cell lines, and polyamine depletion has been shown to be a viable...
Show morePolyamines are small cationic molecules that play important roles in most vital cellular processes including cell growth and proliferation, regulation of chromatin structure, translation and programmed cell death. Cellular polyamine pools are maintained by a balance between biosynthesis and transport (export and import). Increased polyamine biosynthesis activity and an active transport system are characteristics of many cancer cell lines, and polyamine depletion has been shown to be a viable anticancer strategy. Polyamine levels can be depleted by ?-difluoromethylornithine (DFMO), an inhibitor of the key polyamine biosynthesis enzyme ornithine decarboxylase. However, malignant cells often circumvent DFMO therapy by up-regulating polyamine import; therefore, there is a need to develop compounds that inhibit polyamine transport. Collectively, DFMO and polyamine transport inhibitors provide the basis for a combination therapy leading to effective intracellular polyamine depletion. Using a Drosophila leg imaginal disc model for polyamine transport, I studied three candidate transport inhibitors (Ant444, Trimer44 and Triamide44) for their ability to inhibit transport in the Drosophila model. Ant444 and Trimer44 effectively inhibited the uptake of the toxic polyamine analog Ant44 that gains entry to cells via the polyamine transport system. Ant444 and Trimer44 were also able to inhibit the import of exogenous polyamines into DFMO-treated imaginal discs. Triamide44 was an ineffective inhibitor, however a structurally redesigned compound, Triamide444, showed a 50-fold increase in transport inhibition and was comparable to Ant444 and Trimer44. Ant444 and Trimer44 showed differences in their relative abilities to block import of specific polyamines, and I therefore asked if a cocktail of these inhibitors would be more effective than either alone. My data show that a cocktail of polyamine transport inhibitors is more effective than single inhibitors when used in combination with DFMO, and suggests the existence of multiple polyamine transport systems. To further the development of effective transport inhibitors it is important to identify components of the transport system. The mechanism of polyamine transport in multicellular organisms including mammals is still unknown. Our laboratory has developed a simple assay to detect components of the transport system using RNAi knockdown and over-expression of candidate genes. However, the assay requires that animals live until the pupal stage of development. Pleiotropic effects of individual gene products following over-expression or knockdown may result in early developmental lethality for reasons unrelated to polyamine transport. Our assay is based on the GAL4/UAS system and involves the use of enhancers driving GAL4 expression (GAL4 driver). GAL4 in turn determines the expression level of UAS-candidate gene constructs (UAS responder). I reasoned that in some cases it might be possible to bypass early lethality by judicious choice of drivers that reduce responder expression, thus permitting survival to the pupal phase. To this end, I used five imaginal disc drivers (30A, 71B, 32B, 69B, and T80) as well as a ubiquitously expressed control driver to over-express and knockdown EGFR and components of the Rho signaling pathway. The relative strength of each driver was ranked, and I was able to demonstrate in principle that animals could survive to later stages of development in a manner that correlated with the relative strength of the driver. The approach I developed is broadly applicable to other studies of Drosophila development.To identify new components of the polyamine transport system I studied the role of proteoglycans in this process. The proteoglycan glypican-1 has been previously implicated in mammalian polyamine transport. In particular, the heparin sulfate side chains of glypican-1 appear to play an important role. In order to extend our knowledge of the role of proteoglycans in polyamine transport, I examined the role of the core proteoglycans perlecan and syndecan as well as genes encoding enzymes in the heparin sulfate and chondroitin sulfate biosynthetic pathways. I was able to confirm a role for glypican-1 in polyamine transport in imaginal discs but not in whole animals. This may indicate that glypican-1 is not required for polyamine uptake through the gut. Studies of genes encoding perlecan, syndecan and enzymes in the heparin sulfate and chondroitin sulfate biosynthetic pathways did not reveal a role for these genes in polyamine transport. These studies were conducted in whole animals and my data may reflect tissue-specific differences between the imaginal disc and gut transport systems where transport in imaginal discs is proteoglycan dependent and transport in the gut is not.
Show less - Date Issued
- 2017
- Identifier
- CFE0007297, ucf:52162
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007297
- Title
- Discovery and characterization of novel antimicrobials against Mycobacterium tuberculosis.
- Creator
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Rodrigues Felix, Carolina, Rohde, Kyle, Jewett, Mollie, Self, William, Phanstiel, Otto, University of Central Florida
- Abstract / Description
-
Tuberculosis disease is currently a global health emergency, causing the most deaths worldwide due a single infectious agent. Eradication of TB is hampered by lack of an effective vaccine and poor treatment options. During infection, host-derived cues such as hypoxia and starvation induce Mycobacterium tuberculosis to halt replication and become dormant, which leads to tolerance to front-line antibiotics used in the TB treatment. This dormant phenotype causes delayed clearance of M....
Show moreTuberculosis disease is currently a global health emergency, causing the most deaths worldwide due a single infectious agent. Eradication of TB is hampered by lack of an effective vaccine and poor treatment options. During infection, host-derived cues such as hypoxia and starvation induce Mycobacterium tuberculosis to halt replication and become dormant, which leads to tolerance to front-line antibiotics used in the TB treatment. This dormant phenotype causes delayed clearance of M. tuberculosis, therefore a long treatment time is required for stable cure without relapse. Poor patient compliance increases the emergence of drug resistant strains, posing yet another challenge for the eradication of TB. There is dire need for novel compounds targeting not only drug-resistant, but also dormant bacteria so as to effectively eliminate drug-resistant strains and also shorten treatment time. This requires compounds with novel modes of action and novel drug screening approaches which focus on dormant M. tuberculosis. In the current work a method was optimized which induces the dormant phenotype of M. tuberculosis in vitro allowing large scale screening of compounds against these tolerant bacteria. The high chemical diversity of marine natural products was explored to increase the chances of finding novel compounds with novel mechanisms of action. Additionally, gold-complexed scaffolds were examined for their putative ability to inhibit topoisomerase 1, which is a highly conserved and essential protein of mycobacteria, not currently targeted in classical treatment regimens. Several marine natural products were identified with selective bactericidal activity against dormant bacteria, emphasizing the powerful tool that was developed for drug screening. Moreover, the gold-complexes were also bactericidal against not only replicating and dormant bacilli, but also mycobacteria resistant to front-line TB drugs. Compounds characterized in this study represent a promising starting point for the development of novel TB therapeutics and discovery of new conditionally essential pathways of dormant bacteria.
Show less - Date Issued
- 2017
- Identifier
- CFE0007294, ucf:52172
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007294
- Title
- Improved system for fabrication and characterization of nanophotonic devices by multi-photon lithography.
- Creator
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Sharma, Rashi, Kuebler, Stephen, Zou, Shengli, Huo, Qun, Beazley, Melanie, Phanstiel, Otto, University of Central Florida
- Abstract / Description
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A new system for multi-photon lithography (MPL) was developed and used to fabricate three-dimensional (3D) structures with higher aspect ratio, better resolution, improved fidelity, and reduced structural distortion relative to a conventional implementation of MPL.A set of curved waveguides (Rbend = 19 (&)#181;m, and 38 (&)#181;m) and straight waveguides (length = 50 (&)#181;m, Rbend = ?) were fabricated in an epoxide photopolymer and optically characterized using light having a wavelength in...
Show moreA new system for multi-photon lithography (MPL) was developed and used to fabricate three-dimensional (3D) structures with higher aspect ratio, better resolution, improved fidelity, and reduced structural distortion relative to a conventional implementation of MPL.A set of curved waveguides (Rbend = 19 (&)#181;m, and 38 (&)#181;m) and straight waveguides (length = 50 (&)#181;m, Rbend = ?) were fabricated in an epoxide photopolymer and optically characterized using light having a wavelength in vacuum of ?0 = 2.94 (&)#181;m. The optical performance of the waveguides was compared to novel spatially-variant photonic crystals (SVPCs) previously studied in the group. The waveguides were found to guide light with 90% lower efficiency, due to mode leakage. The study provides further evidence that SVPCs operate not through total internal reflection, but rather through self-collimation, as designed.3D uniform-lattice photonic crystals (ULPCs) were fabricated by MPL using a commercial acrylate photopolymer. The ULPCs were optically characterized at ?0 = 1.55 (&)#181;m. A laser beam with adjustable bandwidth was used to measure the self-collimation in the ULPCs. For the low bandwidth beam, vertically polarized light was self-collimated, whereas horizontally polarized light diverged. The transmission efficiency of the ULPCs was also measured as a function of fill factor. The ULPC having a fill factor of 48% exhibited 80% transmission.An etching process was also developed for non-destructively removing Au/Pd coatings that must be deposited onto structures to image them by scanning electron microscopy. The structural and optical integrity of the samples was found to be maintained despite etching. The sputter-coated sample sustained no structural damage when exposed to the ?0 = 1.55 (&)#181;m. However, the metal coating resulted in diminished transmission efficiency due to the high reflection of the 1.55 (&)#181;m beam by the metal coating.
Show less - Date Issued
- 2018
- Identifier
- CFE0007767, ucf:52380
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0007767
- Title
- Design, Synthesis, and Biological Evaluation of Novel Polyamine Transport System Probes and their Application to Human Cancers.
- Creator
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Muth, Aaron, Phanstiel, Otto, Ye, Jingdong, Elsheimer, Seth, Miles, Delbert, Vonkalm, Laurence, University of Central Florida
- Abstract / Description
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The mammalian polyamine transport system (PTS) has been of interest due to its roles in cancer and maintaining cellular homeostasis. Polyamines are essential growth factors which are tightly controlled via a balance of biosynthesis, metabolism, import, and export. This work focused on the development and biological testing of polyamine transport probes to help understand the molecular requirements of the PTS. This was mediated through the use of a CHO (PTS active) and CHO-MG* (PTS deficient)...
Show moreThe mammalian polyamine transport system (PTS) has been of interest due to its roles in cancer and maintaining cellular homeostasis. Polyamines are essential growth factors which are tightly controlled via a balance of biosynthesis, metabolism, import, and export. This work focused on the development and biological testing of polyamine transport probes to help understand the molecular requirements of the PTS. This was mediated through the use of a CHO (PTS active) and CHO-MG* (PTS deficient) screen, where compounds demonstrating high toxicity in CHO and low toxicity in CHO-MG* were considered PTS selective. The first chapter focused on the development of polyamine-based drugs which are both metabolically stable to polyamine oxidase (PAO) activity and are hyperselective for targeting the PTS. This approach was optimized by combining a di-substituted aryl design with terminal N-methylation of the appended polyamine chains to generate a new class of superior PTS agonists. The metabolic stability of these compounds was demonstrated in CHO and CHO-MG* in the presence and absence of a known PAO inhibitor, aminoguanidine (AG). Highly PTS selective compounds were then tested in the NCI-60 cell line screen to demonstrate the effectiveness of polyamine-based drugs in cancer therapy. During this screen, the MALME-3M (human melanoma) cell line was identified as being very sensitive to these PTS targeting drugs. Further studies using MALME-3M and its normal counterpart, MALME-3, showed excellent targeting of the cancer line over MALME-3. For example, The MeN44Nap44NMe compound showed 59-fold higher toxicity in MALME-3M over MALME-3.The second chapter focused on the development of potential polyamine transport inhibitors (PTIs) for use in combination therapy with ?-difluoromethylornithine (DFMO). This therapy is predicated upon reducing sustained polyamine depletion within cells by inhibiting both polyamine biosynthesis with DFMO and polyamine transport with the PTI ligand. Potential PTIs were identified by blocking the uptake of spermidine in DFMO-treated CHO and L3.6pl cells. Previous work has identified a tri-substituted polyamine-based design as an effective PTI. Low toxicity and a low Ki value in a L1210 screen were good predictors for PTI efficacy. The structural requirements for a potent PTI were explored by modulating the toxicity through the introduction of amide bonds, and also by determining the number and orientation of the polyamine messages (appended to an aryl core) required for efficient inhibition of polyamine uptake. These experiments showed that a tri-substituted design and a triamine message (homospermidine) appended was optimal for PTI potency. The final chapter focused on the development of Dihydromotuporamine C derivatives as non-toxic anti-metastatic agents. Dihydromotuporamine C demonstrated good anti-invasive properties with tumor cells. Derivatives were made in an effort to reduce the cytotoxicity of the parent and improve the anti-migration potency. The motuporamine derivatives all have a polyamine message (norspermidine or homospermidine) appended to make a macrocycle core, making them prime targets to evaluate as potential PTS ligands in the CHO and CHO-MG* screen. Each compound was also tested in the highly metastatic pancreatic cancer cell line L3.6pl to determine both its IC50 value and maximum tolerated dose (MTD). The anti-migration assay was performed at the lowest MTD obtained (0.6 (&)#181;M) in order to compare the series at the same non-toxic dose. The results suggested that as the N1-amine center was moved further from the macrocyclic ring, an increased ability to inhibit cell migration and reduced toxicity was observed. These collective findings provide new tools for cell biologists to modulate and target polyamine transport in mammalian cells. Future applications of these technologies include new cancer therapies which are cell-selective and inhibit the spread of tumors.
Show less - Date Issued
- 2012
- Identifier
- CFE0004636, ucf:49895
- Format
- Document (PDF)
- PURL
- http://purl.flvc.org/ucf/fd/CFE0004636
